IL-18 is a proinflammatory cytokine that is elevated in HIV-1 infection (7, 8) and is thought to contribute to HIV/AIDS pathogenesis by inducing Th2 cytokine production (12, 13). IL-18 and IL-1beta are structurally related cytokines that require caspase-1 cleavage for processing and release (3, 5). Intracellular bacterial activation of a multi-protein complex known as the inflammasome has been implicated in caspase-1 activation and IL-beta processing and release (21). We hypothesized that HIV-1 infection of monocyte derived macrophages (MDMs) can induce inflammasome activation, leading to IL-18/IL-1beta processing and release. Aim #1 will address this hypothesis by a series ELISA, Western Blots, immunoprecipitation and immunodepletion experiments. Aim #2 will address the mechanism by which HIV-1 may induce inflammasome activation. We postulated that HIV-1 may activate the inflammasome by inducing inflammasome gene expression or by having a direct interaction with an inflammasome component. We will test both of these mechanisms by a series of Real Time PCR, gene delivery, siRNA, immunoprecipitation, Western Blot and immunodepletion experiments. Taken together, the results from these experiments will provide a better understanding of the mechanisms by which HIV-1 infection induces high levels of IL-18 secretion and may lead to new avenues for therapeutic intervention.